Exploring ACSL4/LPCAT3/ALOX15 and SLC7A11/GPX4/NFE2L2 as Potential Targets in Ferroptosis-Based Cancer Therapy

Gupta, Gaurav; Bhat, Asif Ahmad; Goyal, Ahsas; Singla, Neelam; Gupta, Saurabh; Sharma, Sanjay; Bhatt, Shvetank; Dua, Kamal

doi:10.4155/fmc-2023-0125

Cited by 24 publications

(6 citation statements)

References 18 publications

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“…ACSL4 is responsible for converting polyunsaturated fatty acids (PUFAs) into their respective acyl-CoAs and plays a crucial role in maintaining PUFA-containing membrane phospholipids (PUFA-PLs) 22 . LPCAT3 and AGPAT3 demonstrate a specific preference for PUFA-CoA as their substrate 5,23,24 . By increasing the levels of PUFA-PLs or PUFA-containing ether phospholipids (PUFA-ePLs), they enhance the susceptibility of cancer cells to ferroptosis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Novel Ferroptosis Inducer with Dual Modulatory Effects on GPX4 Activity and Stability

Wang,

Liao,

Yang

et al. 2023

Preprint

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Ferroptosis is a unique form of intracellular iron-dependent cell death that differs from apoptosis, necrosis, and autophagy. GPX4, an antioxidant defense enzyme, plays a pivotal role as regulator of ferroptosis. Extensive researches suggest that targeting GPX4 holds promise for cancer therapy. However, the current GPX4 inhibitors face challenges due to unfavorable drug-like properties, which hinder their progress in clinical development. In this study, we identified a novel inhibitor called MI-2, demonstrating potent ferroptosis-inducing capacity. Mechanistically, MI-2 effectively inhibits the activity of GPX4 by direct interaction. Furthermore, MI-2 promotes the degradation of GPX4 through its well-established target, MALT1. In multiple cancer models, MI-2 has demonstrated synergistic effects when combined with sorafenib or regorafenib, resulting in enhanced ferroptosis induction. These findings highlight the dual modulatory effects of MI-2 on GPX4 activity and stability, offering a promising starting point for the development of drug-like GPX4 inhibitors with translational potential.

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Section: Resultsmentioning

confidence: 99%

Identification of a Novel Ferroptosis Inducer with Dual Modulatory Effects on GPX4 Activity and Stability

Wang,

Liao,

Yang

et al. 2023

Preprint

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“…SQSTM1 plays a role in selective autophagy ( Tian et al, 2013 ), which is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. Other than cancer cells or certain types of epithelial cells ( Gupta et al, 2023 ), emerging research suggests that neurons can undergo ferroptosis and autophagy ( Dong et al, 2022 ; Duan et al, 2023 ) under certain conditions ( Liang et al, 2022 ; Yang et al, 2023 ). Ferroptosis and autophagy in neurons have been implicated in various neurodegenerative diseases, including AD.…”

Section: Discussionmentioning

confidence: 99%

Reduced GLP-1R availability in the caudate nucleus with Alzheimer’s disease

Barrett,

Ivey,

Cunningham

et al. 2024

Front. Aging Neurosci.

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The glucagon-like peptide-1 receptor (GLP-1R) agonists reduce glycated hemoglobin in patients with type 2 diabetes. Mounting evidence indicates that the potential of GLP-1R agonists, mimicking a 30 amino acid ligand, GLP-1, extends to the treatment of neurodegenerative conditions, with a particular focus on Alzheimer’s disease (AD). However, the mechanism that underlies regulation of GLP-1R availability in the brain with AD remains poorly understood. Here, using whole transcriptome RNA-Seq of the human postmortem caudate nucleus with AD and chronic hydrocephalus (CH) in the elderly, we found that GLP-1R and select mRNAs expressed in glucose dysmetabolism and dyslipidemia were significantly altered. Furthermore, we detected human RNA indicating a deficiency in doublecortin (DCX) levels and the presence of ferroptosis in the caudate nucleus impacted by AD. Using the genome data viewer, we assessed mutability of GLP-1R and 39 other genes by two factors associated with high mutation rates in chromosomes of four species. Surprisingly, we identified that nucleotide sizes of GLP-1R transcript exceptionally differed in all four species of humans, chimpanzees, rats, and mice by up to 6-fold. Taken together, the protein network database analysis suggests that reduced GLP-1R in the aged human brain is associated with glucose dysmetabolism, ferroptosis, and reduced DCX+ neurons, that may contribute to AD.

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“…In cells, PUFAs and coenzyme A (CoA) are catalyzed by Acyl‐CoA synthetase long‐chain family member 4 (ACSL4) to form the corresponding PUFAs‐CoA. Afterwards, with the assistance of lysophosphatidylcholine acyltransferase 3 (LPCAT3), PUFAs‐CoA binds to lysophosphatidylethanolamine (LysoPE) to form PE‐PUFAs, which are oxidized to peroxides under the induction of 15‐lipoxygenase (LOX15), thereby promoting the occurrence and development of ferroptosis 50 . The reconstruction pathway is on the phospholipid membrane.…”

Section: Ferroptosismentioning

confidence: 99%

The association between ferroptosis and autophagy in cardiovascular diseases

Zhang,

Yang,

Ouyang

et al. 2024

Cell Biochemistry & Function

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Autophagy is a process in which cells degrade intracellular substances and play a variety of roles in cells, such as maintaining intracellular homeostasis, preventing cell overgrowth, and removing pathogens. It is highly conserved during the evolution of eukaryotic cells. So far, the study of autophagy is still a hot topic in the field of cytology. Ferroptosis is an iron‐dependent form of cell death, accompanied by the accumulation of reactive oxygen species and lipid peroxides. With the deepening of research, it has been found that ferroptosis, like autophagy, is involved in the occurrence and development of cardiovascular diseases. The relationship between autophagy and ferroptosis is complex, and the association between the two in cardiovascular disease remains to be clarified. This article reviews the mechanism of autophagy and ferroptosis and their correlation, and discusses the relationship between them in cardiovascular diseases, which is expected to provide new and important treatment strategies for cardiovascular diseases.

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Exploring ACSL4/LPCAT3/ALOX15 and SLC7A11/GPX4/NFE2L2 as Potential Targets in Ferroptosis-Based Cancer Therapy

Cited by 24 publications

References 18 publications

Identification of a Novel Ferroptosis Inducer with Dual Modulatory Effects on GPX4 Activity and Stability

Identification of a Novel Ferroptosis Inducer with Dual Modulatory Effects on GPX4 Activity and Stability

Reduced GLP-1R availability in the caudate nucleus with Alzheimer’s disease

The association between ferroptosis and autophagy in cardiovascular diseases

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